This invention relates to an antithrombogenic/antibiotic containing plastic material and process for making the same. More particularly, the invention relates to a method for preparing an antithrombogenic/antibiotic plastic material which employs a novel solvent system containing chloroflurocarbon compounds and petroleum ether.
Extensive investigations have been undertaken over many years to find materials that will be biologically and chemically stable towards body fluids. This area of research has become increasingly important with the development of various objects and articles which can be in contact with blood, such as artificial organs, vascular grafts, probes, cannulas, catheters, hyperalimentation catheters and other long indwelling vascular catheters and the like.
Artificial materials are being increasingly used as blood contact devices and may be subject to potential generation of thrombus and bacterial infection. When blood contacts foreign materials a complex series of events occur. These involve protein deposition, cellular adhesion and aggregation, and activation of blood coagulation schemes. Considerable research effort has been focused on this blood-material-interaction in the last twenty years as well as bacterial infection associated with such devices. The overall objective of these investigations has been to minimize the potential for thrombus formation and reduce potential bacterial infection found on the foreign materials, such as the device when introduced into the body upon contact with blood.
Various methods have been devised for producing such a material, most of which involve chemically bonding a quarternary ammonium salt to the polymer and then heparinizing the same. Separately antibiotics have been coupled to these devices using similar techniques. Usually, this is done by incorporating an amine in the polymer, quaternizing the amine, and then heparinizing or bonding an antibiotic to the quarternized material.
In one method taught by R. I. Leininger and G. A. Grode, U.S. Pat. No. 3,457,098, a quaternary amine is incorporated into an epoxy resin. Subsequent exposure to sodium heparinate dissolved in water then results in ionically bound heparin. The polymer systems are essentially epoxy resins which are rigid polymers which are not suitable for forming medical devices such as catheters or other devices requiring extrusion. These polymers also are not appropriate where flexibility in the device is required.
R. I. Leininger and R. D. Falb disclose in U.S. Pat. No. 3,617,344 another process for binding heparin. This system differs from the previous system in that low molecular weight chloromethyl groups are absorbed to the surface of a polymer substrate. Subsequent amination by a tertiary amine and quaternization resulted in a positively charged surface for binding with heparin. The concept, in general, embodies the use of low molecular weight quaternized groups to ionically bind heparin.
U.S. Pat. No. 3,846,353 to H. M. Grotta involves use of long chain alkyl quaternary amines on the surface of a polymer wherein the positively charged surface is exposed to a solution of sodium heparinate. The amines are dissolved in an organic solvent consisting of toluene, petroleum ether and mixtures thereof. The primary deficiency of the Grotta method is the use of toluene as a coating solvent. Toluene, when used with latex materials, results in a swelling of the products and destruction of essential elastic properties, rendering itself practically useless. In particular, this effect is seen with balloons present on balloon catheters wherein the balloon component becomes extremely fragile and is basically destroyed. Additionally, it is known that toluene is carcinogenic. Residues of toluene that may remain on the devices from processing which are targeted for internal use are thus harmful to the ultimate user.
S-P. S. Yen and A. Rembaum prepared a neutral polyurethane elastomer which is subsequently quaternized and ionically bonded to heparin, U.S. Pat. No. 3,853,804. The main disadvantage of this system is that it is a chemical complex and toxic solvents are used to achieve solubility when coating. The coating technique, however, is difficult to perform due to the solvent (DMF) requirement. The patent of N. Harumiya et al., U.S. Pat. No. 3,844,989, describes a polymer composition of waterinsoluble cationic copolymers having hydrophilic components, quarternary amine groups, and hydrophobic moieties. Heparin is bonded ionically to the quaternary ammonium groups via absorption after the polymer components are contacted with a heparin solution. This method involves use of complex synthesis procedures and is not readily applicable to coating other polymeric or non-polymeric materials.
Greco, et al. in U.S. Pat. No. 4,442,133, teaches a method of preparing a surgical vascular graft wherein a length of graft material carries an adsorbed coating of tridodecylmethylammonium chloride (TDMAC) surfactant and an antibiotic bound thereto. A length of graft material such as polytetrafluoroethylene or Dacron is soaked in a 5% benzalkonium chloride solution of TDMAC for 30 minutes at room temperature, air dried and then washed in distilled water to remove excess TDMAC. The use of such aromatic solvents are not fully acceptable because they are alcohol soluble and water swellable and can be more brittle than the long chain alkyl coupling agents.
It would be desirable to provide a material which has excellent biological and chemical stability towards body fluids, namely blood, and which retains its antithrombogenic agent and antibiotic effect for a long term while being slowly leachable when in contact with blood. It would also be desirable to provide materials which, when made, use solvent systems that are safe and non-carcinogenic not only for the manufacturer but also for the ultimate user.
The present invention accomplishes all of these needs by use of a particular organic solvent system containing specific chlorofluorocarbons and petroleum ether. More particularly, the invention involves a method for making an antithrombogenic/antibiotic plastic material, which comprises: exposing the polymeric plastic material to an organic solvent system containing dissolved therein a quaternary ammonium compound, said organic solvent system consisting essentially of (1) a chlorofluorocarbon selected from the group consisting of 1,1,2-trichloro-1,2,2-trifluoroethane; 1,2-difluoro-1,1,2,2-tetracloroethane; 1,1-difluoro-1,2,2,2-tetrachloroethane; and mixtures thereof (2) petroleum ether, wherein the components are present in a parts ratio ranging from 9 to 1 parts chlorofluorocarbon to 1 part petroleum ether; and thereafter exposing said polymeric polymer surface to a solution of a material selected from an antithrombogenic agent, an antibiotic agent or mixtures thereof.
In another embodiment, the present invention relates to devices containing an antithrombogenic/antibiotic material prepared by the novel process of this invention.
The term antithrombogenic agent or material as used herein refers to any material which inhibits thrombus formation on its surface, such as by reducing platelet aggregation, dissolving fibrin, enhancing passivating protein deposition, or inhibiting one or more steps within the coagulation cascade and which form an ionic complex with quaternary ammonium salts. Illustrative antithrombogenic materials may be selected from the group consisting of heparin, prostaglandins, sulfated polysaccharide, and mixtures thereof. Heparin is preferred. It should be understood that these materials are used in their natural form or as salts thereof, such as the sodium, or lithium salt. In addition to the foregoing antithrombogenic agents, optional supplemental amounts of antithrombogenic agents may also be used that are not reactive within the scope of the invention to further enhance the effects of the materials. Exemplary materials include urokinase, streptokinase, albumin and so forth.
The term antibiotic agent or material as used herein refers to any material which inhibits bacterial infection. Illustrative antibiotic materials may be selected from a wide range of material that have a reactive carboxyl functionality. Exemplary materials may be selected from the group consisting of penicillin, oxacillin, ticarcillin, carbenicillin, cephalosporins, cefoxitin, cefazolin, dicloxacillin, cloxacillin, and clavulanic acid (or salt form), and mixtures thereof.
The plastic materials used in the invention as the support structure may be selected from a wide range of polymeric material. The particular formations do not constitute a critical aspect of this invention other than to serve as a support substrate for the antithrombogenic agent/antibiotic agent.
Illustrative plastic materials may be selected from the group consisting of polyethylene, polypropylene, polyurethanes, polyurethane-silicone copolymers, polyurethane-ureas, polycarbonates, silicone rubber, polyesters, nylons, natural rubber, polyvinyl chloride, acrylics, polystyrene, copolymers of polycarbonate and silicone rubber and mixtures thereof. The plastic materials are preferably preformed into the desired shape or structure for the particular application prior to treatment according to the invention. Of significant importance is the ability of the support to adhere with the antithrombogenic/antibiotic agents without becoming deformed when the organic solvent is applied to the substrate.
A particularly preferred family of quaternary ammonium compounds useable in the invention are long chain alkyl quaternary ammonium salts. The salt may have 2 to 4 long chain alkyl groups attached to the nitrogen atom, the alkyl groups having from about 10 to about 30 carbon atoms. The alkyl groups can be like or unlike. The remaining groups may be hydrogen, lower alkyl, aryl and aryl alkyl groups. The ammonium cation is not critical and is preferably chlorine. These compounds are generally obtained by heating together a tertiary amine and an alkylating agent to thereby produce the quaternary ammonium salt by standard techniques well known to the ordinary skilled artisan. Preferred quaternary ammonium compounds are selected from the group consisting of tridodecylmethyl ammonium salts, and tetradodecyl ammonium salts and mixtures thereof. The organic solvent system used to prepare the final material is a critical feature of this invention. The organic solvent system must be able to solubilize the quaternary ammonium compound without solubilizing the plastic material; that is, it must be compatible with the plastic support. The solvent system must be capable of being rapidly removed from the plastic material once exposure to the system is complete. In addition, the system must be noncarcinogenic and be nonswelling when contacting is complete; that is, the solvent must not react with or modify the physical properties of the plastic material. A unique combination of ingredients has been discovered which is able to achieve all of these results. The solvent system is composed of two main ingredients, a chlorofluorocarbon and petroleum ether. It has been found that the chlorofluorocarbon may be selected from the group consisting of 1,1,2-trichloro-1,2,2-trifluoroethane, 1,2-difluoro-1,1,2,2-tetrachloroethane, 1,1-difluoro-1,2,2,2-tetrachloroethane, and mixtures thereof.
Another critical feature of the invention is the ratio of the chlorofluorocarbon to the petroleum ether. It has been found necessary to employ in the organic solvent system at least 50% of the chlorofluorocarbon. Preferably, the chlorofluorocarbon to petroleum ether ratio is employed in a parts ratio ranging from 9 to 1 parts chlorofluorocarbon to 1 part petroleum ether. This ratio has been found suitable to obtain maximum dissolution of the quaternary ammonium chloride and an appropriate amount of ionically complexed material, e.g., antithrombogenic, antibiotic and mixtures thereof. At ratios above 9 parts chlorofluorocarbon, incomplete dissolution occurs rendering the final plastic material unacceptable for the intended purpose.
The amount of quaternary ammonium compound dissolved in the organic solvent system may vary widely and is preferably used in amounts of about 0.25% to about 15% by weight of the organic solvent system. Amounts below or above this range may be useable but have been found not to be preferred. This amount of material includes the use of quaternary ammonium compound alone or when it is prereacted to form a complex with the antithrombogenic agent and/or antibiotic agent. The method for performing this prereaction is considered well known and within the skill of the ordinary artisan.
Once the quaternary ammonium compound is dissolved in the organic solvent system, the plastic material is contacted with the solution such as by exposing the contacting surface to the solution. No particular contacting time is necessary. All that is necessary is that the surface be simply exposed, such as by dip coating or spray coating. The solvent is then removed by simple evaporation at ambient conditions.
After removal of the solvent system the quaternary ammonium compound is contacted with the antithrombogenic material and/or antibiotic. This may be conveniently done by dissolving the active material in water or other appropriate solution and re-expose the plastic material with the solution. Contacting may be performed for 1 to 30 minutes to enable ionic coupling of the active material to the quaternary ammonium compound. Excess solution is removed and the product dried. Drying is performed to remove the solvent without inactivating the antithrombogenic agent and/or antibiotic agent. This may be done in a heated oven at temperatures from 40.degree. to 60.degree. C., or air drying overnight. The manner in which the product is dried is considered well known and within the skill of the ordinary artisan.
As an alternate embodiment, the quaternary ammonium compound is prereacted with the active material; namely, antithrombogenic agent and/or antibiotic material. Once prereacted the ionic complex is dissolved in the organic solvent system described above and the surface of the plastic material exposed to the solution. Solvent evaporation then takes place and the product is ready for use or storage.
The plastic material once prepared has a thin passive coating layer or film of the quaternary ammonium compound which is ionically coupled to the antithrombogenic agent/antibiotic agent. The coating resembles a thin film which enables the active component to be slowly leached from the film. This slow leaching effort inhibits bacterial infection when an antibiotic is used and thrombus formation when an antithrombogenic agent is used, or both.
One particularly preferred plastic material is polyurethane polymers which may contain conventional polyisocyanates, low molecular weight glycols and high molecular weight glycols.
The polyisocyanates useful in the invention in introducing the urethane linkage into the polymer chain may be selected from a wide range of aliphatic, cycloalipathic and aromatic polyisocyanates. Useable diisocyanates may contain noninterfering groups, e.g., aliphatic hydrocarbon radicals such as lower alkyl or other groups, having substantially nonreactive hydrogens as determined by the Zerewitinoff test, J. Am. Chem. Soc. 49,3181 (1927). The diisocyanate often has at least 6 carbon atoms and usually does not have more than about 40 carbon atoms. Diisocyanates of about 8 to 20 atoms in the hydrocarbon group are preferred. Suitable diisocyanates include 2,4-toluene diisocyanate; 2,6-toluene diisocyanate; 1,4-cyclohexane diisocyanate; dicyclohexylmethane 4,4'-diisocyanate; xylene diisocyanate; 1-isocyanate-3-isocyanatomethyl-3,5,5-trimethylcyclohexane; hexamethylene diisocyanate; methylcyclohexyl diisocyanate; 2,4,4-trimethylhexyl-methylene diisocyanate, isocyanates such as m-phenylene diisocyanate; mixtures of 2,4- and 2,6 hexamethylene-1,5-diisocyanate; hexahydrotolylene diisocyanate (and isomers), naphtylene-1,5-diisocyanate; 1-methoxyphenyl 2,4-diisocyanate; diphenylmethane 4,4'-diisocyanate; 4,4'biphenylene diisocyanate; 3,3'-dimethoxy-4.4biphenyl diisocyanate; 3,3'dimethyl-4,4'-biphenyl diisocyanate; and 3,3'dimethyl-diphenylmethane-4,4'diisocyanate and mixtures thereof. The aliphatic and alicyclic diisocyanates employed in the process of this invention and the products made therefrom generally exhibit good resistance to the degradative effects of ultraviolet light.
The polyisocyanate compound used to form the prepolymers may contain a portion of polyisocyanates having more than two isocyanate (NCO) groups per molecule providing the urethane polymer compositions are not unduly deleteriously affected. The preferred polyisocyanate is selected from the group consisting of 4,4'-diphenylmethane diisocyanate, toluene diisocyanate, isophorone diisocyanate and methylene bis(4-cyclohexyl) diisocyanate.
The low molecular weight glycols may also be used to prepare the prepolymer which materials may have from 2 to 10 carbon atoms. Exemplary of these glycols are ethylene glycol, diethylene glycol, triethylene glycols, 1,4-butanediol, neopentyl glycol, 1,6-hexanediol, 1,2- and 1,3-propylene glycol, 2,3-butylene glycol, cyclohexane dimethanol (1,4-bis hydroxymethyl cyclohexane), dipropylene glycol, and dibutylene glycol.
The high molecular weight glycols useful in the present invention may be a polyether diol or polyester diol and range in number average molecular weight from about 400 to 3,000 and preferably about 500 to about 2,000. Examples of suitable polyhydric alcohols are ethylene glycol, 1,2- and 1,3-propylene glycol, 1,4- and 2,3-butylene glycol, 1,6-hexane diol, 1,8-octane diol, neopentyl glycol, cyclonexane dimethanol (1,4-bishydroxy methyl cyclohexane), 2-methyl-1,3-propane diol, also diethylene glycol, triethylene glycol, tetraethylene glycol, polyethylene glycols, dipropylene glycol, polypropylene glycols, dibutylene glycol and polybutylene glycols. Polyesters of lactones, for example, .epsilon.-caprolactone or hydroxy carboxylic acids, for example, .omega.-hydroxycaproic acid, may also be used. Illustrative polyesters may contain hydroxyl groups, for example, reaction products of polyhydric alcohols reacted with divalent carboxylic acids. It is also possible to use the corresponding polycarboxylic acid anhydrides or corresponding polycarboxylic acid esters of lower alcohols or mixtures thereof, for producing the polyesters. The polycarboxylic acids may be aliphatic, cycloaliphatic, aromatic and/or heterocyclic and may optionally be substituted, for example, by halogen atoms and/or unsaturated. Examples of polycarboxylic acids of this kind include succinic acid, adipic acid, suberic acid, azelaic acid, sebacic acid, phthalic acid, phthalic acid anhydride, tetrachlorophthalic acid anhydride, endomethylene tetrahydrophthalic acid anhydride, glutaric acid anhydride, maleic acid, maleic acid anhydride, fumaric acid, dimeric and trimeric fatty acids such as oleic acid, optionally in admixture with monomeric fatty acids, terephthalic acid dimethyl ester and terephthalic acid dimethyl ester and terephthalic acid bis-glycol ester.
The polyethers containing at least 2, generally 2 to 8, but preferably 2 to 3 hydroxyl groups used in accordance with the invention are also known per se and are obtained, for example, by polymerizing epoxides, such as ethylene oxide, propylene oxide, butylene oxide, tetrahydrofuran, styrene oxide or epichlorohydrin on their own, for example, in the presence of BF.sub.3, or by adding these epoxides, optionally in admixture or in succession, to starter components containing reactive hydrogen atoms, such as water, alcohols, or amines, for example, ethylene glycol, 1,3- or 1,2-propylene glycol, 4,4'-dihydroxy diphenyl propane, aniline, ammonia, ethanolamine or ethylene diamine. The most preferred polyether diols are poly(tetramethylene ether) glycols.
While the preferred polyurethane compositions of the invention are thermoplastic, it has been found possible to employ small amounts of crosslinking agents to the compositions when they are coated onto the support in order to render them thermosetting. Suitable crosslinking agents are discussed above and include the listed diisocyanate compounds.
It should be recognized that the products of this invention are useable in a wide variety of devices designed for contacting body fluids. Exemplary articles which can be in contact with body fluids such as blood, include artificial organs, vascular grafts, probes, cannulas, catheters, hemodialysis tubing, hyperalimentation catheters and other long indwelling vascular catheters, and the like. A particularly preferred application, of the products of the invention is in catheter type devices wherein the active agent is coated on either or both interior and exterior surfaces of the catheter.
As a preferred embodiment, the invention involves the preparation of balloon catheters using the solvent system of this invention. Without being limited hereto, a preferred procedure would involve the following steps: a latex or polyurethane balloon catheter is exposed to a solution of quaternary amineantithrombogenic or antibiotic agent wherein the agent has a concentration of 0.1% to 5% (weight by weight). The quaternary ammonium compound may be selected from tridodecylmethyl ammonium salts, tetradodecyl ammonium salts and tridodecylbenzyl ammonium salts along with the organic solvent system containing (1) a chlorofluorocarbon selected from the group consisting of 1,1,2-trichloro-1,2,2-trifluoroethane; 1,2-difluoro-1,1,2,2-tetrachloroethane; 1,1-difluoro-1,2,2,2-tetrachloroethane, and mixtures thereof; (2) and petroleum ether wherein the components are present in a parts ratio of 9 to 1:1.
The antithrombogenic or antibiotic agent may be present in concentrations ranging from 5% to 60% by weight of the quaternary amine-antithrombogenic/antibiotic complex.
After exposure to the solution the balloon catheter is quickly removed and the solvent is allowed to evaporate at room temperature. The catheters are then packaged and stored for use.
The invention will be further illustrated by the following non-limiting examples. All parts and percentages given throughout the specification are by weight unless otherwise indicated.